| First Author | Mezza T | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 41 | Pages | 21485-21495 |
| PubMed ID | 27535223 | Mgi Jnum | J:237303 |
| Mgi Id | MGI:5811961 | Doi | 10.1074/jbc.M116.735738 |
| Citation | Mezza T, et al. (2016) Nuclear Export of FoxO1 Is Associated with ERK Signaling in beta-Cells Lacking Insulin Receptors. J Biol Chem 291(41):21485-21495 |
| abstractText | The insulin/insulin-like growth factor (IGF) signaling pathway plays a critical role in the regulation of islet cell biology. However, the signaling pathway(s) utilized by insulin to directly modulate beta-cells is unclear. To interrogate whether insulin exerts endocrine effects in regulating proteins in the insulin/IGF-1 signaling cascade in vivo in physiological states via the insulin receptor, we designed two experimental approaches: 1) glucose gavage and 2) hyperinsulinemic intravenous infusion, for studies in either beta-cell specific insulin receptor knock-out (betaIRKO) or control mice. Immunostaining of sections of pancreas (collected immediately after glucose gavage or insulin infusion) from controls showed significant increases in pAKT+, p-p70S6K+, and pERK+ beta-cells and a significant decrease in % nuclear FoxO1+ beta-cells compared with corresponding vehicle-treated groups. In contrast, in betaIRKOs, we observed no significant changes in pAKT+ or p-p70S6K+ beta-cells in either experiment; however, pERK+ beta-cells were significantly increased, and an attenuated decrease in % nuclear FoxO1+ beta cells was evident in response to glucose gavage or insulin infusion. Treatment of control and betaIRKO beta-cell lines with glucose or insulin showed significantly decreased % nuclear FoxO1+ beta-cells suggesting direct effects. Furthermore, blocking MAPK signaling had virtually no effect on FoxO1 nuclear export in controls, in contrast to attenuated export in betaIRKO beta-cells. These data suggest insulin acts on beta-cells in an endocrine manner in the normal situation; and that in beta-cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling. |
